TP53 Functional-Domain-Specific Mutations Define Distinct Clinical Outcomes in EGFR-Mutant Non-Small Cell Lung Cancer...

Area of Science:

• Oncology
• Genetics
• Molecular Biology

Background:

• EGFR tyrosine kinase inhibitors (EGFR-TKIs) improve outcomes in advanced non-small cell lung cancer (NSCLC) with sensitizing EGFR mutations.
• Clinical outcomes vary based on EGFR mutation subtype and TP53 co-mutations.
• Previous studies often treated TP53 status as binary, limiting understanding of domain-specific alterations.

Purpose of the Study:

• To investigate the prognostic significance of TP53 alterations, specifically domain involvement, in EGFR-mutant NSCLC treated with first-line EGFR-TKIs.
• To assess the impact of TP53 mutation location on progression-free survival (PFS).
• To explore the interaction between TP53 domain alterations, EGFR mutation subtypes, and TKI generation.

Main Methods:

• Retrospective analysis of advanced NSCLC patients with sensitizing EGFR mutations receiving first-line EGFR-TKI therapy.
• Classification of EGFR mutations into common (exon 19 deletion, L858R) and uncommon types.
• Categorization of TP53 alterations into DNA-binding domain (DBD)-involved, other TP53 mutations, and TP53 wild type (TP53-WT).

Main Results:

• TP53 alterations, primarily in the DBD, were found in about half the cohort.
• Third-generation EGFR-TKIs showed longer PFS than first- or second-generation TKIs, especially in TP53-mutant tumors.
• TP53 DBD-involved mutations were associated with significantly shorter PFS compared to other TP53 mutations or TP53-WT, particularly with common EGFR mutations and older TKIs.

Conclusions:

• TP53 functional domain involvement offers prognostic value beyond simple mutation status in EGFR-mutant NSCLC.
• TP53 DBD-involved alterations identify a high-risk subgroup with poorer PFS, especially when treated with first- or second-generation EGFR-TKIs.
• Integrating TP53 domain classification with EGFR mutation subtypes can enhance risk stratification and treatment planning for EGFR-mutant NSCLC.